High-throughput screening approaches are ubiquitious in the pharmaceutical industry as part of the drug discovery process. A variety of sensors are used in these screens, the most common of which are spectroscopic. Such absorbance or fluorescence based high-throughput screens inevitably require the use of extrinsic probes to provide a signal, and often require labeling of the target receptor or the test ligand. Binding reactions are then monitored indirectly, grom changes in the optical properties of the extrinsic label. We propose the design and production of a high-throughput differential scanning calorimeter (HT-DSC) for use in drug discovery. Calorimetry offers a significant advantage over spectroscopic approaches in that it directly monitors heat changes for binding reactions without the need for receptor modification or labeling. Heat is a "universal signal" that can not only detect binding reactions qualitatively but can also be used to dgorously quantify binding reactions by providing detailed thermodynamic information. In this Phase I project period, we will complete the detailed design plans for a 100 cell array differential scanning calorimeter with sensitivity and sample sizes comparable to existing single-cell biocalorimeters that are commercially available. We will complete demonstration experiments using DNA and protein binding reactions to illustrate the advantages of array calorimetry, using existing prototype 16-cell and 100-cell HTDSC instruments. Finally we will begin development of assay protocols for specific DNA and protein reactions for use in Phase II of this project when production prototype HT-DSC instruments will be produced and tested.